Indanyl thiocarbamates



United States Patent ABSTRACT OF THE DISCLOSURE Compounds of the formula wherein X is O or CH R is hydrogen, allyl, lower alkyl, halogen, or lower alkoxy, R is hydrogen, allyl or lower alkyl and R is adamantyl or e 5 Quiz;

wherein Y and Y are hydrogen, allyl, lower alkyl, halogen or lower alkoxy and may be the same or difierent, are active antifungal compounds. Preferably, X is CH R is hydrogen, R is methyl, R" is m-tolyl, and the OCSN(R)R" is in the fi-position.

This invention relates to new organic compounds having valuable pharmaceutical actitvity and to a process for the preparation of said compounds.

In particular, the invention relates to thioacarbamates having the structure wherein X is O or CH R is hydrogen, allyl, lower alkyl, lower alkoxy or halogen, R is hydrogen, allyl or lower alkyl, and R is adamantyl or "ice wherein Y and Y are hydrogen, allyl, lower alkyl, lower alkoxy or halogen and may be the same or different. The lower alkyl groups contain up to 5 carbon atoms and may be methyl, ethyl, isopropyl, butyl, secbutyl, amyl, isoamyl and the like. The lower alkoxy groups also contain up to 5 carbons and may be methoxy, ethoxy, isopropoxy, butoxy, and the like.

Preferably X is CH R is hydrogen, R is methyl, R" is m-tolyl, and the OCSN(R)R group is in the beta position.

According to the process of this invention the compounds are prepared by the reaction in the presence of an alkaline substance of an amine of the formula with a thionochloroformate of the formula wherein X, R, R, and R are the same as above. Suitable alkaline substances for use in the reaction include sodium or potassium hydroxide, sodium carbonate, sodium bicarbonate, pyridine, triethylamine, and N-methylmorpholine. The reaction is preferably carried out by heating in an inert solvent. The thionochloroformates are readily obtained by the reaction of thiophosgene with a phenol of the desired structure.

The compounds of this invention have strong topical antifungal activity and may be administered topically in the form of ointments and solutions.

The invention will be more fully understood from the examples which follow, and it is intended to cover all changes and modifications of the examples of the invention herein chosen for purposes of disclosure which do not depart from the spirit and scope of the invention.

EXAMPLE I O- S-indanyl) -m,N-dimethyl-thionocarbanilate 9.7 g. N-methyl-m-toluidine and 6.7 g. NaHCO were added to ml. acetone. 17 g. S-idanyl-thionochoroformate was added to the resulting mixture at about 0l0 C. The mixture was refluxed for about 15 minutes, cooled and poured into cc. water. The solid which precipitated was recrystallized and melted at 9495 C.

Following the procedure in Example I, the following compounds were prepared (all substituted in the fl-position, except compound F which was substituted in the wherein IZ-POSitiOD): R is hydrogen, aliyl lower alkyl, lower-alkoxy,-or

x n R. R M.P. (deg) A on, B'Br CH; 07-100 B on, H on. 114-115 o on; H CH; Q01 135-131 D o H on, 100402 E OH; H H adamantyl 178-180 F on, on, 90-91 EXAMPLE H bromine,

An ointment cream suitable for topical administration was prepared by mixing thoroughly the following ingredients:

Each gram of the ointment cream contained 10 mg. of the active ingredient.

EXAMPLE III A nonaqueous solution suitable for topical administration was prepared by dissolving 10 g. of O-(5-indanyl)- m,N-dimethyl-thionocarbanilate in 800 ml. propylene glycol. 1 g. of butylated hydroxytoluene was added, and the solution brought to 1000 ml. by the addition of propylene glycol. The resulting clear, homogeneous solution had a concentration of 1% of the active ingredient.

Compounds of the formula Ar'OCSN(R)-Ar wherein Ar and Rr' are aryl and R is alkyl have been disclosed as possessing anti-fungal activity (French Patent No. 1,337,797). Preferably, R is methyl, Ar is m-tolyl, and Ar is B-naphthyl (Noguchi et al., Antimicrobial Agents and Chemothereapy, 1962, 259. The replacement of the fi-naphthyl group by other aryl groups resulted in a great loss of activity, so the high activity obtained when we replaced the naphthalene by an iudan or a benzodioxan was unexpected.

We claim:

1. A compound having the structure R' is hydrogen, allyl, or lower alkyl, and R is adamantyl or References Cited UNITED STATES PATENTS 8/1959 Tilles et a1. 260455 OTHER REFERENCES Reid: Chemistry of Bivalent Sulfur, vol. IV (1962),

Japan Soda Co.: p. 4227.

CHARLES B. PARKER, Primary Examiner D. R. PHILLIPS, Assistant Examiner us. 01. X.R.

Chem. Abstracts, vol. 630965), 

